The ability of drugs to be administered via the oral route depends on several factors. The drug must be soluble in the gastrointestinal fluids in order for the drug to be transported across biological membranes for an active transport mechanism, or have suitable small particle size that can be absorbed through the Peyer's Patches in the small intestine and through the lymphatic system. Particle size is an important parameter when oral delivery is to be achieved (see Couvreur P. et al, Adv. Drug Delivery Reviews 10:141-162, 1993).
The primary issue in the ability to deliver drugs orally is the protection of the drug from proteolytic enzymes. An ideal approach is to incorporate the drug in a hydrophobic material so that the aqueous fluids cannot penetrate the system. Lipid-based cochleates are an ideal system that can achieve this purpose.
The advantages of cochleates are numerous. The cochleates have a nonaqueous structure and therefore they:
a) are more stable because of less oxidation of lipids; PA1 b) can be stored lyophilized which provides the potential to be stored for long periods of time at room temperatures, which would be advantageous for worldwide shipping and storage prior to administration; PA1 c) maintain their structure even after lyophilization, whereas liposome structures are destroyed by lyophilization; PA1 d) exhibit efficient incorporation of hydrophobic drugs into the lipid bilayer of the cochleate structure; PA1 e) exhibit efficient incorporation of antigens with hydrophobic moieties into the lipid bilayer of the cochleate structure; PA1 f) have the potential for slow release of a drug, antigen or biologically relevant molecule in vivo as cochleates dissociate; PA1 g) have a lipid bilayer which serves as a carrier and is composed of simple lipids which are found in animal and plant cell membranes, so that the lipids are non-toxic; PA1 h) are produced easily and safely; PA1 i) can be produced as defined formulations composed of predetermined amounts and ratios of drugs or antigens. PA1 a) a drug component, PA1 b) a negatively charged lipid, and PA1 c) a divalent cation component,
Cochleate structures have been prepared first by D. Papahadjopoulos as an intermediate in the preparation of large unilamellar vesicles (see U.S. Pat. No. 4,078,052). The use of cochleates to deliver protein or peptide molecules for vaccines has been disclosed in U.S. Pat. No. 5,840,707. However, neither of these patents addresses the importance of particle size or the effective oral delivery of drug mediated by small-sized cochleates.